The nuclear receptor (NR) superfamily constitutes a group of 48 transcription factors in humans, which includes the receptors for steroid hormones, thyroid hormone, lipophilic vitamins, and cholesterol metabolites. Approximately half of NRs are classified as orphan receptors since they do not have well characterized ligands. Thus, a large number of NRs have no validated chemical tools to use to probe the function of these receptors in vivo. This is a critical need given that virtually all the NRs that have identified ligands are well-characterized targets for the development of drugs to treat myriad diseases including cancer, diabetes, atherosclerosis, inflammation, and endocrine/reproductive disorders. The estrogen-related orphan receptors have been implicated in a range of physiological processes including lipid and glucose metabolism, mitochondrial function, cellular proliferation/cancer, bone formation, muscle fiber type determination, vascularization, inflammation and deafness. Thus, synthetic ligands targeting these receptors may hold utility in treatment of myriad human disorders including obesity and type 2 diabetes, cardiovascular disease (atherosclerosis), cancer, osteoporosis, inflammation, and deafness. We have developed a novel, first-in-class ERR? agonist that display limited in vivo activity. Here, we describe our plans for optimization of ERR? synthetic agonists for use as chemical tools to probe the function of these receptors in vivo as well as to determine potential utility of targeting this receptor for treatment of diseases associated with skeletal muscle dysfunction, in particular muscular dystrophy.